Glucosamine is a well-known amino monosaccharide found in chitin, glycoproteins and glycosaminoglycans. Glucosamine is widely used for the treatment of rheumatic fever, arthritic and arthosic complaints, in the acute as well as chronic forms, as well as in the treatment of pathological conditions originating from metabolic disorders of the osteo-articular tissue. Although products in the marketplace are labeled as, or referred to as, “glucosamine”, they are misnomers since such products consist of glucosamine hydrochloride or as unreacted mixtures of glucosamine hydrochloride and a salt such as potassium or sodium sulfate.
Mixed salts of glucosamine hydrochloride and alkaline or earth alkaline metal sulfates such as potassium sulfate, and sodium sulfate are well known. Such mixed salts are used rather than glucosamine sulfate alone since the latter is unstable in view of its highly hygroscopic nature and the facility with which its amino group oxidizes if not completely saltified, see, e.g., U.S. Pat. No. 4,642,340 and U.S. Pat. No. 3,683,076 which disclose mixtures of glucosamine sulfate and glucosamine hydroiodide.
In EP 0 214 642, five glucosamine base containing residual chloride is converted to a mixed salt of glucosamine sulfate and potassium chloride by dissolving the glucosamine base in water, adding a stoichiometric quantity of concentrated sulfuric acid to form a solution of glucosamine sulfate in water and dissolving a stoichiometric amount of potassium chloride in the solution. The mixed salt is precipitated from the solution by addition of a precipitant such as isopropanol, stirring the mixture for about 14 hours to complete the precipitation, cooling the reaction mass to 0° C. and recovering the precipitated salt by filtration. This process results in low yields.
Free glucosamine base may be prepared by the method recited in Chem. Ber., volume 75, page 1274. Such method involves the treatment of glucosamine hydrochloride with an ethanolic solution of a tertiary base such as triethylamine. Triethylamine hydrochloride is filtered off and the free glucosamine is then recovered from the reaction mixture. However, triethylamine is a toxic material even in small quantities and the yield of the free glucosamine base is quite low. Moreover, the free glucosamine base still contains residual chloride.
Free glucosamine base may also be prepared by microbial fermentation. For example, see U.S. Published Patent Application Publication Nos. 2004/0091976 A1, 2004/0077055 A1 and 2003/0148998 A1. It is known to prepare glucosamine by deacetylation of n-acetylglucosamine, see U.S. Published Patent Application Publication No. 2005/0145846 A1. Glucosamine hydrochloride may also be prepared by the process disclosed in U.S. Pat. No. 6,486,307; the process involves the grinding of chitin to a very fine size, followed by digestion with concentrated hydrochloric acid. The crude glucosamine hydrochloride is then decolorized with activated charcoal and assayed by pH titration with a base.
In U.S. Published Patent Application 2004/0030121, free glucosamine base containing residual chloride is converted to a mixed salt of glucosamine sulfate and potassium chloride by dissolving the glucosamine base in water, adding a stoichiometric quantity of concentrated sulfuric acid to form a solution of glucosamine sulfate in water and dissolving a stoichiometric amount of potassium chloride in the solution. The mixed salt is precipitated from the solution by addition of a precipitant such as isopropanol, stirring the mixture for about 14 hours to complete the precipitation, cooling the reaction mass to 0° C. and recovering the precipitated salt by filtration. This process results in low yields.
Regardless of the source of the glucosamine, it is commercially available only in the form of a halide salt, usually the hydrochloride, since the glucosamine free base can only be isolated from aqueous reaction mixtures in the form of its salt. Furthermore, free glucosamine base is unstable at ambient temperatures and is quite hygroscopic and it is therefore converted to a halide salt before being marketed.
It would be most desirable if a method could be found for converting a glucosamine halide into a halide-free glucosamine base. The resultant halide-free glucosamine base could then be used as is for those medicinal purposes in which the presence of a salt such as sodium or potassium chloride, sodium or potassium sulfate, sodium or potassium iodide, etc. is undesirable. The halide-free glucosamine base may also be employed to prepare a wide variety of useful derivatives such as glucosamine salts, e.g., glucosamine sulfate, glucosamine phosphate, glucosamine salts of α-hydroxy acids (e.g., lactic acid, citric acid, etc.), n-acetylglucosamine, glucosamine salts of drugs having acidic functionalities, etc., wherein such derivatives and salts do not contain any objectionable cations such as sodium or potassium.